Obesity and Body Weight

2026-08-12 · Hansen MEB, et al. American Journal of Human Genetics 2026, PMID:42586059

Anthropometric and cardio-metabolic trait variation and genetic associations in sub-Saharan Africa

Hansen MEB, et al. (American Journal of Human Genetics, 2026) is newly in the GWAS Catalog, with 166 associations across 21 traits — an atlas rather than a single question. The catalogue records its sample as 1,544 individuals. Of its 106 positions, 21 already have pages here — 1 on the Waist Circumference page; 1 on the Childhood Body Mass Index page; 1 on the Obesity and Body Weight page — including rs11636311 (near DUT), rs9920281 (SLC12A1), rs668316 (near LINC01491). Put together by code from the catalogue's records; for anything more, follow the link to the paper. PMID:42586059.

2026-04-08 · 23andMe Research Institute, published in Nature (GWAS of 27,885 GLP-1 drug users)

Genetic predictors of GLP1 receptor agonist weight loss and side effects

A genome-wide study of 27,885 people taking GLP-1 drugs (semaglutide, tirzepatide) found a GLP1R variant linked to an extra 0.76 kg of weight loss per copy of the effect allele (P=2.9x10-10) -- direct genetic evidence the drug's own target gene shapes how well it works, not just a co-mention. The same study tied a GIPR variant (rs1800437, profiled on this site) to worse nausea and vomiting, specifically in people taking tirzepatide.

2025-09-12 · Genome-wide association study provides novel insight into the genetic architecture of severe obesity. PLOS Genetics. 2025. DOI:10.1371/journal.pgen.1011842

Severe obesity (BMI 40+) shares almost all its genetics with ordinary BMI -- with three new exceptions

Severe obesity (SevO) -- Class III (BMI>=40) and Class IV (BMI>=50) -- drives cardiovascular and cardiometabolic disease and several cancers, but remains understudied relative to BMI generally, especially in marginalized populations. This study meta-analyzed the top of the BMI distribution (>=95th percentile) and the two SevO classes across 159,359 people from 11 ancestrally diverse studies, with replication in 480,897 people across 6 more studies. It confirmed a large overlap between the genetic architecture of continuous BMI and severe obesity specifically -- meaning the same common variants driving ordinary weight variation largely explain severe obesity too, not a separate genetic category. Within that overlap, it identified and replicated three genuinely novel signals specific to severe obesity: TENM2, PLCL2 and ZNF184, all within loci already known for BMI generally but newly tied to the severe end of the distribution specifically. Combining functional mapping, polygenic risk scores and phenome-wide association analysis, the study reinforced that known downstream comorbidities and lifestyle-gene interactions apply similarly across the BMI spectrum. This site's obesity and body weight page carries 527 variants; TENM2, PLCL2 and ZNF184 are not currently among them.

2026-03-06 · Haapaniemi H et al. The genetic basis of dermatophytosis skin infection susceptibility. Nature Communications 2026, PMID:41792138

Fungal skin infection runs partly in the genes — and through obesity genes

Dermatophytosis — the fungal infection behind athlete's foot, nail fungus and ringworm — affects around 20% of the world's population. A genome-wide meta-analysis of over 250,000 cases from FinnGen, the Estonian Biobank, UK Biobank and the Million Veteran Program found 30 genome-wide significant loci, with top signals near ZNF646, HLA-DQB1, FLG, FTO, SLURP2 and KRT77, and pointed to keratin biology, the skin barrier, immune function and obesity. 19 of the study's positions already have pages here, including rs1421085 in FTO, the best-known obesity position, and five on the dermatophytosis page. PMID:41792138.

Locus and variant. rs9930506 is an intronic single-nucleotide variant within FTO (alpha-ketoglutarate-dependent dioxygenase FTO; OMIM *610966) at chromosome 16q12.2. It sits within the large first intron of FTO, a region now understood to function as a long-range regulatory element rather than to affect FTO's own enzymatic (RNA demethylase) activity directly.

Discovery and effect size. rs9930506 was identified as the lead FTO variant for body-weight traits in a genome-wide association scan of 4,741–6,148 Sardinian individuals (ages 14–102) from the Lanusei Valley (Scuteri et al., PLoS Genetics 2007; PMID 17658951; GWAS Catalog trait "Obesity-related traits," study GCST000060). It was the most significantly associated FTO SNP for BMI (p = 8.6×10⁻⁷), hip circumference (p = 3.4×10⁻⁸), and weight (p = 9.1×10⁻⁷) in that cohort. Homozygotes for the common allele versus the alternate allele (minor allele frequency ≈ 0.46 in Sardinians) differed by approximately 1.3 BMI units on average; the association replicated in independent GenNet cohorts of European-American (n=1,496) and Hispanic-American (n=839) ancestry with an approximately 1.0 BMI-unit difference between homozygote groups (combined replication p between 0.0005 and 0.001), but did not reach significance in an African-American sample, where the relevant allele frequency was lower (≈0.21) and local linkage disequilibrium patterns differ. A later multi-ancestry meta-analysis (Wojcik et al., Nature 2019; PMID 31217584), incorporating African-American, Hispanic/Latino, Asian, Native Hawaiian, and Native American ancestry cohorts, confirmed genome-wide-significant association of rs9930506 with BMI (β ≈ 0.06 BMI units per copy, 95% CI 0.048–0.076, p = 4×10⁻¹⁸ per GWAS Catalog).

Relationship to other FTO markers. rs9930506 is in strong linkage disequilibrium with rs9939609, the FTO marker used in the landmark Frayling et al. study (Science 2007; PMID 17434869), which found that the 16% of adults homozygous for its risk allele weighed about 3 kg more and had a 1.67-fold higher odds of obesity than non-carriers, with the effect detectable from age 7 onward and reflecting increased fat mass specifically rather than lean mass or height. Because these markers travel together on the same haplotype in much of the genome studied, effect-size figures reported for one closely approximate, but are not identical to, the other. In the 1000 Genomes European-ancestry panel (CEU), the two markers show r² ≈ 0.86 (Ensembl linkage disequilibrium calculator) — strong enough that effect-size estimates for one track closely with the other in European-ancestry cohorts specifically. That correlation is far weaker in populations with African ancestry (r² ≈ 0.05–0.09 in the same panel's ASW, YRI and MSL samples), part of why the association has not replicated as consistently in African-American cohorts.

Proposed mechanism. Functional work by Claussnitzer et al. (NEJM 2015; PMID 26287746) traced a causal mechanism to a different but nearby FTO-intron variant, rs1421085, showing that its risk allele disrupts a repressor binding motif (ARID5B), de-represses a preadipocyte enhancer, and roughly doubles expression of two adjacent genes, IRX3 and IRX5, during early adipocyte differentiation. This shifts precursor cells away from thermogenic ("beige/brite") fat and toward energy-storing white fat, reducing mitochondrial thermogenesis roughly fivefold in cell models; CRISPR correction of rs1421085 restored thermogenic gene expression. Because rs9930506 lies in the same regulatory haplotype block, it is generally interpreted as a marker in linkage with this regulatory mechanism rather than a demonstrated causal variant in its own right; appetite/satiety effects mediated via hypothalamic FTO/FTM circuitry have also been proposed and are not mutually exclusive with the adipocyte mechanism.

Population variation and equity caveat. Effect-allele frequency for FTO obesity-associated variants differs substantially by ancestry (common in European, South Asian, and some African populations; generally lower average BMI effect reported in East Asian cohorts for some correlated markers), and most large discovery cohorts have been of European ancestry, so caution is warranted before generalizing point estimates across all populations.

Diagnostic context. Clinical obesity is defined by BMI thresholds (BMI ≥30 kg/m² in most adult clinical guidelines) or by direct adiposity measures, never by genotype; rs9930506 and related FTO markers are population risk-modifiers used in research and polygenic risk contexts, not diagnostic or predictive tests for any individual.